A randomized, double-blind study on the efficacy of oral domperidone versus placebo for reducing SARS-CoV-2 viral load in mild-to-moderate COVID-19 patients in primary health care.

INTRODUCTION: The clinical effect of domperidone against COVID-19 has been investigated in a double-blind phase III clinical trial (EudraCT number 2021-001228-17). Domperidone has shown in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential immudolatory properties through the stimulation of prolactin secretion. PATIENTS AND METHODS: The efficacy of oral domperidone plus standard of care (SOC; n = 87) versus placebo plus SOC (n = 86) was evaluated in a 28-day randomized double-blind multicentre study in primary health care centres. A total of 173 outpatients with mild-to-moderate COVID-19 were included. Three daily doses of 10 mg (30 mg/day) of domperidone or placebo were administered for 7 days. Reduction of viral load on day 4 was the primary efficay endpoint. It was estimated in saliva samples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), as the cycle thresholds detected ORF1ab, N Protein and S Protein genes. RESULTS: A significant reduction in the viral load was observed (p < 0.001) from baseline to days 4, 7 and 14 of the three genes studied with non-significant differences between domperidone and placebo groups. Twenty-three patients (13.3%) experienced adverse events, 14 patients in the domperidone group (16.1%) and 9 patients in the placebo group (10.5%). No patients needed to be hospitalized. CONCLUSION: Results do not prove the use of domperidone as antiviral in patients with COVID-19.

A 28-day double-blind clinical trial was performed to investigate the antiviral effect of domperidone, 30 mg/day for 7 days (n = 87) versus placebo (n = 86) in outpatients with mild-to-moderate COVID-19.The primary efficacy endpoint was the reduction of viral load on day 4 as compared with baseline, estimated as the cycle thresholds to detect ORF1ab, N Protein and S Protein genes by RT-qPCR in saliva samples.The study findings do not prove the use of domperidone as antiviral in patients with COVID-19.

The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Serum biomarkers for diagnosis and characterization of prostate cancer. / Biomarcadores plasmáticos en el diagnóstico y caracterización del cáncer de próstata.

PSA is the most widely used diagnosticand prognostic biomarker in prostate cancer (PCa).However, its lack of specificity has generated the needto search for new complementary markers. In thisscenario, blood plasma constitutes one of the sourcesof search for new markers, which have been tried tobe combined with PSA and other clinical variables inorder to develop tests that increase their diagnosticspecificity.This narrative review of the literature provides anoverview of commercially available plasma biomarkers and tests for use in different clinical settingsfor PCa. The most studied markers to help select theappropriate patients for initial and / or repeat biopsyhave been: PHI, 4K, STHLM3. These markers havebeen oriented towards the diagnosis of the so-calledclinically signifi cant PCa, trying to validate and calibratetheir algorithms in different populations. Giventhe development and evolution in the diagnosis of PCa,there is still a lack of evidence of the impact of magneticresonance imaging (MRI) when used in combinationwith these new markers, as well as its possiblerole in the screening of the disease and not only in theearly diagnosis process. Furthermore, there are only asmall number of studies that have directly comparedthese tests with each other and with PSA, so there isnot enough evidence to know which test has the bestproperties in each clinical scenario. In order to clarifythe true diagnostic role of these new biomarkers, newprospective, comparative studies in different populationsare absolutely necessary to evaluate their clinicalutility in combination with MRI and fusion biopsy.

El PSA es el biomarcador diagnóstico ypronóstico más ampliamente utilizado en cáncer deprostata (CaP). Sin embargo, su falta de especificidadha generado la necesidad de buscar nuevos marcadorescomplementarios. En este escenario, el plasmasanguíneo constituye una de las fuentes de búsquedade nuevos marcadores, los cuales han tratado decombinarse con el PSA y otras variables clínicas conel objeto de desarrollar tests que aumentaran su especificidaddiagnóstica.En esta revisión narrativa de la literatura se proporcionauna descripción general de los biomarcadoresplasmáticos y tests disponibles comercialmentepara ser utilizados en diferentes contextos clínicosdel CaP. Los test más estudiados para ayudar a seleccionarlos pacientes adecuados para la biopsia inicialy / o repetida han sido: PHI, 4K, STHLM3. Estos testse han orientado hacia el diagnóstico del denominadoCaP clínicamente significativo, intentando validary calibrar sus algoritmos en diferentes poblaciones.Dado el desarrollo y evolución en el diagnóstico deCaP, aún existe una falta de evidencia del impacto de la resonancia magnética (RM) al ser empleada encombinación con estos nuevos marcadores, así comosu posible papel en el screening de la enfermedad yno solo en el proceso de diagnóstico precoz. Además,solo se dispone de una pequeña cantidad de estudiosque hayan comparado directamente estos test entreellos y con el PSA, de modo que no existe evidenciasuficiente para saber qué test tiene mejores propiedadesen cada escenario clínico. En el escenarioactual, para poder aclarar el verdadero papel diagnósticode estos nuevos biomarcadores, son absolutamentenecesarios nuevos estudios prospectivos,comparativos y en diferentes poblaciones, que evalúensu utilidad clínica en combinación con la RM yla biopsia fusión.

Biomarcadores plasmáticos en el diagnóstico y caracterización del cáncer de próstata / Serum biomarkers for diagnosis and characterization of prostate cáncer

El PSA es el biomarcador diagnóstico y pronóstico más ampliamente utilizado en cáncer deprostata (CaP). Sin embargo, su falta de especificidadha generado la necesidad de buscar nuevos marcadores complementarios. En este escenario, el plasmasanguíneo constituye una de las fuentes de búsqueda de nuevos marcadores, los cuales han tratado decombinarse con el PSA y otras variables clínicas conel objeto de desarrollar tests que aumentaran su especificidad diagnóstica.En esta revisión narrativa de la literatura se proporciona una descripción general de los biomarcadores plasmáticos y tests disponibles comercialmentepara ser utilizados en diferentes contextos clínicosdel CaP. Los test más estudiados para ayudar a seleccionar los pacientes adecuados para la biopsia inicialy / o repetida han sido: PHI, 4K, STHLM3. Estos testse han orientado hacia el diagnóstico del denominado CaP clínicamente significativo, intentando validary calibrar sus algoritmos en diferentes poblaciones.Dado el desarrollo y evolución en el diagnóstico deCaP, aún existe una falta de evidencia del impacto de la resonancia magnética (RM) al ser empleada encombinación con estos nuevos marcadores, así comosu posible papel en el screening de la enfermedad yno solo en el proceso de diagnóstico precoz. Además,solo se dispone de una pequeña cantidad de estudiosque hayan comparado directamente estos test entreellos y con el PSA, de modo que no existe evidenciasuficiente para saber qué test tiene mejores propiedades en cada escenario clínico. En el escenarioactual, para poder aclarar el verdadero papel diagnóstico de estos nuevos biomarcadores, son absolutamente necesarios nuevos estudios prospectivos,comparativos y en diferentes poblaciones, que evalúen su utilidad clínica en combinación con la RM yla biopsia fusión. (AU)

PSA is the most widely used diagnosticand prognostic biomarker in prostate cancer (PCa).However, its lack of specificity has generated the needto search for new complementary markers. In thisscenario, blood plasma constitutes one of the sourcesof search for new markers, which have been tried tobe combined with PSA and other clinical variables inorder to develop tests that increase their diagnosticspecificity.This narrative review of the literature provides anoverview of commercially available plasma biomarkers and tests for use in different clinical settingsfor PCa. The most studied markers to help select theappropriate patients for initial and / or repeat biopsyhave been: PHI, 4K, STHLM3. These markers havebeen oriented towards the diagnosis of the so-calledclinically signifi cant PCa, trying to validate and calibrate their algorithms in different populations. Giventhe development and evolution in the diagnosis of PCa,there is still a lack of evidence of the impact of magnetic resonance imaging (MRI) when used in combination with these new markers, as well as its possiblerole in the screening of the disease and not only in theearly diagnosis process. Furthermore, there are only asmall number of studies that have directly comparedthese tests with each other and with PSA, so there isnot enough evidence to know which test has the bestproperties in each clinical scenario. In order to clarifythe true diagnostic role of these new biomarkers, newprospective, comparative studies in different populations are absolutely necessary to evaluate their clinicalutility in combination with MRI and fusion biopsy. (AU)

Does Adding Standard Systematic Biopsy to Targeted Prostate Biopsy in PI-RADS 3 to 5 Lesions Enhance the Detection of Clinically Significant Prostate Cancer? Should All Patients with PI-RADS 3 Undergo Targeted Biopsy?

INTRODUCTION: Our aim was to assess the value of adding standard biopsy to targeted biopsy in cases of suspicious multiparametric magnetic resonance imaging (mp-MRI) and also to evaluate when a biopsy of a PI-RADS 3 lesion could be avoided. METHODS: A retrospective study of patients who underwent targeted biopsy plus standard systematic biopsy between 2016-2019 was performed. All the 1.5 T magnetic resonance images were evaluated according to PI-RADSv.2. An analysis focusing on the clinical scenario, lesion location, and PI-RADS score was performed. RESULTS: A total of 483 biopsies were evaluated. The mean age was 65 years, with a PSA density of 0.12 ng/mL/cc. One-hundred and two mp-MRIs were categorized as PI-RADS-3. Standard biopsy was most helpful in detecting clinically significant prostate cancer (csPCa) in patients in the active surveillance (AS) cohort (increasing the detection rate 12.2%), and in peripheral lesions (6.5%). Adding standard biopsy showed no increase in the detection rate for csPCa in patients with PI-RADS-5 lesions. Considering targeted biopsy in patients with PI-RADS 3 lesions, a higher detection rate was shown in biopsy-naïve patients versus AS and in patients with a previous negative biopsy (p = 0.002). Furthermore, in these patients, the highest rate of csPCa detection was in anterior lesions [42.9% (p = 0.067)]. CONCLUSIONS: Our results suggest that standard biopsy could be safely omitted in patients with anterior lesions and in those with PI-RADS-5 lesions. Targeted biopsy for PI-RADS-3 lesions would be less effective in peripheral lesions with a previous negative biopsy.

Role of Multiparametric Prostate Magnetic Resonance Imaging before Confirmatory Biopsy in Assessing the Risk of Prostate Cancer Progression during Active Surveillance.

OBJECTIVE: To evaluate the impact of multiparametric magnetic resonance imaging (mpMRI) before confirmatory prostate biopsy in patients under active surveillance (AS). MATERIALS AND METHODS: This retrospective study included 170 patients with Gleason grade 6 prostate cancer initially enrolled in an AS program between 2011 and 2019. Prostate mpMRI was performed using a 1.5 tesla (T) magnetic resonance imaging system with a 16-channel phased-array body coil. The protocol included T1-weighted, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging sequences. Uroradiology reports generated by a specialist were based on prostate imaging-reporting and data system (PI-RADS) version 2. Univariate and multivariate analyses were performed based on regression models. RESULTS: The reclassification rate at confirmatory biopsy was higher in patients with suspicious lesions on mpMRI (PI-RADS score ≥ 3) (n = 47) than in patients with non-suspicious mpMRIs (n = 61) and who did not undergo mpMRIs (n = 62) (66%, 26.2%, and 24.2%, respectively; p < 0.001). On multivariate analysis, presence of a suspicious mpMRI finding (PI-RADS score ≥ 3) was associated (adjusted odds ratio: 4.72) with the risk of reclassification at confirmatory biopsy after adjusting for the main variables (age, prostate-specific antigen density, number of positive cores, number of previous biopsies, and clinical stage). Presence of a suspicious mpMRI finding (adjusted hazard ratio: 2.62) was also associated with the risk of progression to active treatment during the follow-up. CONCLUSION: Inclusion of mpMRI before the confirmatory biopsy is useful to stratify the risk of reclassification during the biopsy as well as to evaluate the risk of progression to active treatment during follow-up.

Role of Multiparametric Prostate Magnetic Resonance Imaging before Confirmatory Biopsy in Assessing the Risk of Prostate Cancer Progression during Active Surveillance

Objective@#To evaluate the impact of multiparametric magnetic resonance imaging (mpMRI) before confirmatory prostate biopsy in patients under active surveillance (AS). @*Materials and Methods@#This retrospective study included 170 patients with Gleason grade 6 prostate cancer initially enrolled in an AS program between 2011 and 2019. Prostate mpMRI was performed using a 1.5 tesla (T) magnetic resonance imaging system with a 16-channel phased-array body coil. The protocol included T1-weighted, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging sequences. Uroradiology reports generated by a specialist were based on prostate imagingreporting and data system (PI-RADS) version 2. Univariate and multivariate analyses were performed based on regression models. @*Results@#The reclassification rate at confirmatory biopsy was higher in patients with suspicious lesions on mpMRI (PI-RADS score ≥ 3) (n = 47) than in patients with non-suspicious mpMRIs (n = 61) and who did not undergo mpMRIs (n = 62) (66%, 26.2%, and 24.2%, respectively; p < 0.001). On multivariate analysis, presence of a suspicious mpMRI finding (PI-RADS score ≥ 3) was associated (adjusted odds ratio: 4.72) with the risk of reclassification at confirmatory biopsy after adjusting for the main variables (age, prostate-specific antigen density, number of positive cores, number of previous biopsies, and clinical stage). Presence of a suspicious mpMRI finding (adjusted hazard ratio: 2.62) was also associated with the risk of progression to active treatment during the follow-up. @*Conclusion@#Inclusion of mpMRI before the confirmatory biopsy is useful to stratify the risk of reclassification during the biopsy as well as to evaluate the risk of progression to active treatment during follow-up.

Role of Multiparametric Prostate Magnetic Resonance Imaging before Confirmatory Biopsy in Assessing the Risk of Prostate Cancer Progression during Active Surveillance

Objective@#To evaluate the impact of multiparametric magnetic resonance imaging (mpMRI) before confirmatory prostate biopsy in patients under active surveillance (AS). @*Materials and Methods@#This retrospective study included 170 patients with Gleason grade 6 prostate cancer initially enrolled in an AS program between 2011 and 2019. Prostate mpMRI was performed using a 1.5 tesla (T) magnetic resonance imaging system with a 16-channel phased-array body coil. The protocol included T1-weighted, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging sequences. Uroradiology reports generated by a specialist were based on prostate imagingreporting and data system (PI-RADS) version 2. Univariate and multivariate analyses were performed based on regression models. @*Results@#The reclassification rate at confirmatory biopsy was higher in patients with suspicious lesions on mpMRI (PI-RADS score ≥ 3) (n = 47) than in patients with non-suspicious mpMRIs (n = 61) and who did not undergo mpMRIs (n = 62) (66%, 26.2%, and 24.2%, respectively; p < 0.001). On multivariate analysis, presence of a suspicious mpMRI finding (PI-RADS score ≥ 3) was associated (adjusted odds ratio: 4.72) with the risk of reclassification at confirmatory biopsy after adjusting for the main variables (age, prostate-specific antigen density, number of positive cores, number of previous biopsies, and clinical stage). Presence of a suspicious mpMRI finding (adjusted hazard ratio: 2.62) was also associated with the risk of progression to active treatment during the follow-up. @*Conclusion@#Inclusion of mpMRI before the confirmatory biopsy is useful to stratify the risk of reclassification during the biopsy as well as to evaluate the risk of progression to active treatment during follow-up.

Variables predictoras del empoderamiento familiar en prácticas de atención temprana centradas en la familia / Predictor variables of family empowerment in family-centred early intervention

OBJETIVO: Determinar algunas de las variables predictoras de empoderamiento familiar en los servicios de atención temprana que implementan prácticas centradas en la familia. MÉTODO: Se plantea en una muestra de 431 familias que reciben servicios de atención temprana en España, un análisis de regresión lineal múltiple, para definir la relación entre las siguientes variables: tipo de prácticas en atención temprana, nivel de apoyos, estatus socioeconómico y diagnóstico de su hijo/a, como predictoras de empoderamiento familiar. RESULTADOS: Los resultados evidencian diferencias significativas entre el empoderamiento de las familias y los apoyos con los que cuentan, también se observan niveles de empoderamiento diferentes en relación al diagnóstico del hijo o la hija con trastornos del neurodesarrollo. CONCLUSIONES: A partir de los resultados, se sugiere reflexionar sobre las prácticas de atención temprana de profesionales en general y logopedas en particular, para potenciar el impacto sobre el empoderamiento de las familias, mejorando la fidelidad en la implementación de prácticas centradas en la familia, y favoreciendo la movilización de recursos y apoyos por parte de la familia, en ese mismo proceso de intervención

OBJECTIVE: To determine some of the predictive variables of family empowerment in early intervention services that implement family-centred practices. METHOD: A multiple linear regression analysis is proposed in a sample of 431 families receiving early care services in Spain, to define the relationship between the following variables: type of early intervention practices, supports, socioeconomic status and diagnosis of their child as predictors of family empowerment. RESULTS: The results show significant differences between the empowerment of the families and the supports they have, and different levels of empowerment are observed in relation to the diagnosis of the son or daughter with neurodevelopmental disorders. CONCLUSIONS: Based on the results, we suggest reflecting on professionals early intervention practices and those of speech therapists in particular, to enhance the impact on empowering families, improving fidelity in the implementation of family-centred practices, and favouring the mobilisation of resources and supports by the family, in that same intervention process

A Single-Center Experience With Third and Fourth Kidney Transplants and Second Kidney Transplant After Pancreas-Kidney Transplant: Surgical Aspects and Outcomes.

OBJECTIVES: Overall, 25% to 33% of patients on kidney transplant wait lists present with prior graft loss. In addition, the number of patients who require a retransplant seems to be increasing. Here, we describe our experience with patients who had a second kidney transplant after a previous pancreas-kidney transplant or a third or fourth kidney transplant. We focused specifically on the technical aspects and outcomes related to this patient group. MATERIALS AND METHODS: A single-center retrospective study was performed. The cohortincluded 15 patients > 18 years old who had received a second kidney graft after pancreas-kidney transplant or a second or greater kidney graft between 2013 and 2019. RESULTS: Median age of recipients was 45 years (range, 20-58 y). In 10 patients, the transperitoneal approach was selected. In 5 patients, the retroperitoneal heterotopic kidney retransplant technique was used. Early surgical complications (≤ 30 days posttransplant) were reported in 4 patients. Three patients had late ureteral stenosis (> 90 days posttransplant). All grafts were functioning at time of patient discharge. Mean creatinine level was 2.69 mg/dL (range, 1.23-6.26 mg/dL). The 1-year and 2-year graft survivalrates were 85% and 75%, respectively. No grafts were lost because of surgical complications. CONCLUSIONS: Retransplant of a second graft after pancreas-kidney transplant or retransplant of a third or fourth renal graft is challenging but feasible, with evidence of reasonably positive outcomes after retransplant.

Observational study comparing the accuracy/variability between the ERSPC and the PCPT risk calculators for the prediction of significant prostate cancer in patients with PSA <10 ng/mL.

INTRODUCTION: Risk calculators (RCs) are easy-to-use tools considering available clinical variables that could help to select those patients with risk of prostate cancer (PCa) who should undergo a prostate biopsy. OBJECTIVE: To perform a comparison for the prediction of significant PCa (SigPCa) between the European Randomised Study of Screening for PCa (ERSPC) and the PCa Prevention Trial (PCPT) RCs in patients with prostate-specific antigen (PSA) between 3 and 10 ng/mL through an evaluation of the accuracy/variability between two consecutive PSA values. SETTING: An observational study in a major university hospital in the south of Spain. METHODS AND PARTICIPANTS: An observational study was performed in patients who underwent a prostate biopsy. SigPCa probabilities were calculated with the two PSA measures using ERSPC3/4+digital rectal examination and PCPT v2+free PSA RCs. The prediction of SigPCa was determined by the area under the receiver operating characteristic curve (AUC). Calibration, discrimination and decision curve analysis were studied. The variability between both RCs' agreement was compared using Cohen's kappa coefficient. RESULTS: 510 patients were analysed (87 diagnosed with SigPCa). The median PSA values were 5.3 and 5 ng/mL for PSA1 and PSA2, respectively. Both RCs overestimated the risk in the case of high-risk probabilities. Discriminative ability for SigPCa was similar between models with an AUC=0.73 (0.68-0.79) for ERSPC-RC versus 0.73 (0.67-0.79) for PCPT-RC. ERSPC-RC showed less variability than PCPT-RC, with a constant agreement (k=0.7-0.8) for usual range of clinical decision-making. Remarkably, a higher number of biopsies would be avoided using the ERSPC-RC, but more SigPCa would be missed along all the risk probabilities. CONCLUSIONS: Both RCs performed similar in the prediction of SigPCa. However, ERSPC-RC seems to be more stable for intraindividual PSA variations.

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells.

Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition.

Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer.

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa.

CE-MS-based urinary biomarkers to distinguish non-significant from significant prostate cancer.

BACKGROUND: Prostate cancer progresses slowly when present in low risk forms but can be lethal when it progresses to metastatic disease. A non-invasive test that can detect significant prostate cancer is needed to guide patient management. METHODS: Capillary electrophoresis/mass spectrometry has been employed to identify urinary peptides that may accurately detect significant prostate cancer. Urine samples from 823 patients with PSA (<15 ng/ml) were collected prior to biopsy. A case-control comparison was performed in a training set of 543 patients (nSig = 98; nnon-Sig = 445) and a validation set of 280 patients (nSig = 48, nnon-Sig = 232). Totally, 19 significant peptides were subsequently combined by a support vector machine algorithm. RESULTS: Independent validation of the 19-biomarker model in 280 patients resulted in a 90% sensitivity and 59% specificity, with an AUC of 0.81, outperforming PSA (AUC = 0.58) and the ERSPC-3/4 risk calculator (AUC = 0.69) in the validation set. CONCLUSIONS: This multi-parametric model holds promise to improve the current diagnosis of significant prostate cancer. This test as a guide to biopsy could help to decrease the number of biopsies and guide intervention. Nevertheless, further prospective validation in an external clinical cohort is required to assess the exact performance characteristics.

Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer.

Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to investigate the association between MetS-components, C-reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig-PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS-diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig-PCa was associated to MetS, greater number of MetS-components and higher CRP levels (odds-ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS-components or CRP levels >2.5 mg/L with an increased Sig-PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology.

Impact of a multidisciplinary team for the management of thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is an important complication associated with several diseases that are rare and life-threatening. TMA is common to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP is defined by a severe deficiency of ADAMTS13, and early treatment is associated with good prognosis. The diagnosis of HUS can be difficult due to the potential multiple etiologies, and the best treatment option in most cases is not well-established yet. The implementation of a multidisciplinary team (MDT) could decrease the time to diagnosis and treatment for HUS and may improve the outcomes of these patients. OBJECTIVE: To determine the impact of MDT on morbidity and mortality [death or chronic renal replacement therapy (CRRT) requirements], incidence and response time [(RT) defined as the period between hospital admission and the first day of direct therapy administration], length of stay at an intensive care unit (ICU-LOS) and total hospitalization (T-LOS) were also assessed. METHODS: We compared a pre-MDT implementation period (from January/2008 to May/2016) versus post-MDT period (from May/2016 to December/2016). The screening TMA diagnosis was made according the following criteria: hemolytic anemia, thrombocytopenia and acute renal damage and without ADAMTS13 deficiency. An online chat was implemented to provide instant medical information. RESULTS: Twenty-eight patients were included. The incidence changed from 2.3 cases/pre-MDT: (all cases: n = 18) to 10 cases/year post-MDT (all cases: n = 10). Two patients died in pre-MDT and post- MDT (11% versus 20%, P = 0.60). From pre-MDT, the number of patients who required CRRT by post-MDT decreased from 7 (39%) to 0, P = 0.03. Similarly, RT, ICU-LOS and T-LOS [median(p25-p75)] decreased from 10 (2-12) days to 0.5 (0-1.5) days, P = 0.04, from 16 (9-30) days to 10 (4-13) days, P = 0.01 and from 33 (22-53) days to 16 (12-32) days, P < 0.01, respectively. CONCLUSION: MDT implementation was associated with a greater number of patients who meet TMA criteria. A decrease in the RT and T-LOS periods were observed and associated with better outcomes in these patients.

Plasma ghrelin O-acyltransferase (GOAT) enzyme levels: A novel non-invasive diagnosis tool for patients with significant prostate cancer.

Early detection of PCa faces severe limitations as PSA displays poor-specificity/sensitivity. As we recently demonstrated that plasma ghrelin O-acyltransferase (GOAT)-enzyme is significantly elevated in PCa-patients compared with healthy-controls, using a limited patients-cohort, we aimed to further explore the potential of GOAT to improve PCa diagnosis using an ample patients-cohort (n = 312) and defining subgroups (i.e. significant PCa/metastatic patients, etc.) that could benefit from this biomarker. Plasma GOAT-levels were evaluated by ELISA in patients with (n = 183) and without (n = 129) PCa. Gleason Score ≥ 7 was considered clinically significant PCa. GOAT-levels were higher in PCa patients vs control patients, and in those with significant PCa vs non-significant PCa. GOAT-levels association with the diagnoses of significant PCa was independent from traditional clinical variables (i.e. PSA/age/DRE). Remarkably, GOAT outperformed PSA in patients with PSA-levels ranging 3-20 ng/mL for the significant PCa diagnosis [GOAT-AUC = 0.612 (0.531-0.693) vs PSA-AUC = 0.494 (0.407-0.580)]. A panel of key variables including GOAT/age/DRE/testosterone also outperformed the same panel but with PSA [AUC = 0.720 (0.710-0.730) vs AUC = 0.705 (0.695-0.716), respectively]. Notably, GOAT-levels could also represent a novel predictive biomarker of aggressiveness, as its levels are positively associated with Gleason Score and the presence of metastasis at the time of diagnoses. Altogether, our data reveal that GOAT-levels can be used as a non-invasive biomarker for significant PCa diagnosis in patients at risk of PCa (with PSA: 3-20 ng/mL).

New Approach to Guide Target Prostate Biopsy: Technique and Initial Experience.

OBJECTIVE: To describe the technique of transrectal biopsy with a new device that fuses multiparametric magnetic resonance (mpMRI) and ultrasound images in real time to guide target biopsies and to evaluate our initial experience. METHODS: Patients with persistent suspicion of prostate cancer despite a previous negative biopsy and who had an mpMRI before the biopsy were selected. All patients underwent target biopsy plus standard systematic biopsy. Significant prostate cancer (sig PCa) was defined according to the Epstein criteria for standard biopsy and Gleason grade of ≥7 and a positive core length of ≥5 mm for target biopsy. RESULTS: The first 40 patients were evaluated. The median age was 65 years old. In a sagittal isotropic sequence, the fusion process was started. The fusion can be improved by using different tools such as concordant points and Global Positioning System corrections tools. In the target biopsy, a median of 4 cores was taken, whereas in the standard biopsy, 12 cores were taken. Twenty-two patients were diagnosed with prostate cancer; of these patients, 17 were diagnosed with sig PCa. The fusion target biopsy diagnosed more sig PCa than the standard biopsy; however, it was not statistically significant (37.5% vs 25%, P=.08). The probability of being diagnosed with cancer increased in correlation with the Prostate Imaging Reporting and Data System score, without reaching statistical significance (k=0.45, P=.08). CONCLUSIONS: This new device is a useful tool to guide biopsy in patients with target lesions in an mpMRI to increase the detection of sig PCa. A larger cohort would be required to show significant differences.

The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness.

BACKGROUND: The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). METHODS: In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). RESULTS: In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. CONCLUSIONS: Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.

sst5TMD4, a splice variant of the sst5 gene, is overexpressed and associated with aggressiveness in various endocrine-related tumors, but its presence, functional role, and mechanisms of actions in prostate cancer (PCa)-the most common cancer type in males-is completely unexplored. In this study, formalin-fixed, paraffin-embedded prostate pieces from patients with localized PCa, which included tumoral and nontumoral adjacent regions (n = 45), fresh biopsies from patients with high-risk PCa (n = 52), and healthy fresh prostates from cystoprostatectomies (n = 14) were examined. In addition, PCa cell lines and xenograft models were used to determine the presence and functional role of sst5TMD4. Results demonstrated that sst5TMD4 is overexpressed (mRNA/protein) in PCa samples, and this is especially drastic in metastatic and/or high Gleason score tumor samples. Remarkably, sst5TMD4 expression was associated with an altered frequency of 2 single-nucleotide polymorphisms: rs197055 and rs12599155. In addition, PCa cell lines and xenograft models were used to demonstrate that sst5TMD4 overexpression increases cell proliferation and migration in PCa cells and induces larger tumors in nude mice, whereas its silencing decreased proliferation and migration. Remarkably, sst5TMD4 overexpression activated multiple intracellular pathways (ERK/JNK, MYC/MAX, WNT, retinoblastoma), altered oncogenes and tumor suppressor gene expression, and disrupted the normal response to somatostatin analogs in PCa cells. Altogether, we demonstrate that sst5TMD4 is overexpressed in PCa, especially in those patients with a worse prognosis, and plays an important pathophysiologic role in PCa, which suggesting its potential as a biomarker and/or therapeutic target.-Hormaechea-Agulla, D., Jiménez-Vacas, J. M., Gómez-Gómez, E., L.-López, F., Carrasco-Valiente, J., Valero-Rosa, J., Moreno, M. M., Sánchez-Sánchez, R., Ortega-Salas, R., Gracia-Navarro, F., Culler, M. D., Ibáñez-Costa, A., Gahete, M. D., Requena, M. J., Castaño, J. P., Luque, R. M. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.